Nucleosides and Nucleotides. 160. Synthesis of Oligodeoxyribonucleotides Containing 5-(N-Aminoalkyl)carbamoyl-2‘-deoxyuridines by a New Postsynthetic Modification Method and Their Thermal Stability and Nuclease-Resistance Properties

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Abstract

Heptadecadeoxynucleotides containing 5-(N-aminoethyl- or N-aminohexyl)carbamoyl-2'-deoxyuridines (E or H) were synthesized using a newly developed postsynthetic modification method. As a convertible nucleoside unit, 5-methoxycarbonyl-2'-deoxyuridine (1) was initially incorporated into oligodeoxynucleotides (ODNs) according to the phosphoramidite method at various positions using a DNA synthesizer. Fully protected ODNs attached to a solid support were treated with alkyldiamines such as ethylenediamine and 1,6-hexanediamine to give the above modified ODNs. The thermal stability, resistance toward nuclease digestion, and stability in fetal calf serum of the modified ODNs were studied. An increase in the number of 5-(N-aminohexyl)carbamoyl-2'-deoxyuridines (H) in the ODNs was found to effectively stabilize duplex formation with both the corresponding complementary DNA and RNA and protect against nucleolytic hydrolysis by snake venom phosphodiesterase. In particular, the half-life of ODN 19, which contained four H residues, was about 162 h in the presence of the nuclease. Furthermore, 19 was also stable in medium containing 10% fetal calf serum with a t1/2 of about 48 h, while t1/2 for the corresponding unmodified ODN was 13 min.

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